The present invention provides nucleoside compounds and certain derivatives thereof which are inhibitors of RNA-dependent RNA viral polymerase. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection. They are particularly useful as inhibitors of hepatitis C virus (HCV) NS5B polymerase, as inhibitors of HCV replication, and for the treatment of hepatitis C infection.
Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world""s population. There are an estimated 4.5 million infected people in the United States alone, according to the U.S. Center for Disease Control. According to the World Health Organization, there are more than 200 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once infected, about 20% of people clear the virus, but the rest harbor HCV the rest of their lives. Ten to twenty percent of chronically infected individuals eventually develop liver-destroying cirrhosis or cancer. The viral disease is transmitted parenterally by contaminated blood and blood products, contaminated needles, or sexually and vertically from infected mothers or carrier mothers to their off-spring. Current treatments for HCV infection, which are restricted to immunotherapy with recombinant interferon-xcex1 alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit. Moreover, there is no established vaccine for HCV. Consequently, there is an urgent need for improved therapeutic agents that effectively combat chronic HCV infection. The state of the art in the treatment of HCV infection has been reviewed, and reference is made to the following publications: B. Dymock, et al., xe2x80x9cNovel approaches to the treatment of hepatitis C virus infection,xe2x80x9d Antiviral Chemistry and Chemotherapy, 11:79-96 (2000); H. Rosen, et al., xe2x80x9cHepatitis C virus: current understanding and prospects for future therapies,xe2x80x9d Molecular Medicine Today, 5:393-399 (1999); D. Moradpour, et al., xe2x80x9cCurrent and evolving therapies for hepatitis C,xe2x80x9d European J. Gastroenterol. Hepatol., 11:1189-1202 (1999); R. Bartenschlager, xe2x80x9cCandidate Targets for Hepatitis C Virus-Specific Antiviral Therapy,xe2x80x9d Intervirology, 40:378-393 (1997); G. M. Lauer and B. D. Walker, xe2x80x9cHepatitis C Virus Infection,xe2x80x9d N. Engl. J. Med., 345:41-52 (2001); B. W. Dymock, xe2x80x9cEmerging therapies for hepatitis C virus infection,xe2x80x9d Emerging Drugs, 6:13-42 (2001); and C. Crabb, xe2x80x9cHard-Won Advances Spark Excitement about Hepatitis C,xe2x80x9d Science: 506-507 (2001); the contents of all of which are incorporated by reference herein in their entirety.
Different approaches to HCV therapy have been taken, which include the inhibition of viral serine proteinase (NS3 protease), helicase, and RNA-dependent RNA polymerase (NS5B), and the development of a vaccine.
The HCV virion is an enveloped positive-strand RNA virus with a single oligoribonucleotide genomic sequence of about 9600 bases which encodes a polyprotein of about 3,010 amino acids. The protein products of the HCV gene consist of the structural proteins C, E1, and E2, and the non-structural proteins NS2, NS3, NS4A and NS4B, and NS5A and NS5B. The nonstructural (NS) proteins are believed to provide the catalytic machinery for viral replication. The NS3 protease releases NS5B, the RNA-dependent RNA polymerase from the polyprotein chain. HCV NS5B polymerase is required for the synthesis of a double-stranded RNA from a single-stranded viral RNA that serves as a template in the replication cycle of HCV. NS5B polymerase is therefore considered to be an essential component in the HCV replication complex [see K. Ishi, et al., xe2x80x9cExpression of Hepatitis C Virus NS5B Protein: Characterization of Its RNA Polymerase Activity and RNA Binding,xe2x80x9d Hepatology, 29:1227-1235 (1999) and V. Lohmann, et al., xe2x80x9cBiochemical and Kinetic Analyses of NS5B RNA-Dependent RNA Polymerase of the Hepatitis C Virus,xe2x80x9d Virology, 249:108-118 (1998)]. Inhibition of HCV NS5B polymerase prevents formation of the double-stranded HCV RNA and therefore constitutes an attractive approach to the development of HCV-specific antiviral therapies.
It has now been found that nucleoside compounds of the present invention and certain derivatives thereof are potent inhibitors of RNA-dependent RNA viral replication and in particular HCV replication. The 5xe2x80x2-triphosphate derivatives of the nucleoside compounds are inhibitors of RNA-dependent RNA viral polymerase and in particular HCV NS5B polymerase. The instant nucleoside compounds and derivatives thereof are useful to treat RNA-dependent RNA viral infection and in particular HCV infection.
It is therefore an object of the present invention to provide nucleoside compounds and certain derivatives thereof which are useful as inhibitors of RNA-dependent RNA viral polymerase and in particular as inhibitors of HCV NS5B polymerase.
It is another object of the present invention to provide nucleoside derivatives which are useful as inhibitors of the replication of an RNA-dependent RNA virus and in particular as inhibitors of the replication of hepatitis C virus.
It is another object of the present invention to provide nucleoside compounds and certain derivatives which are useful in the treatment of RNA-dependent RNA viral infection and in particular in the treatment of HCV infection.
It is another object of the present invention to provide pharmaceutical compositions comprising the novel compounds of the present invention in association with a pharmaceutically acceptable carrier.
It is another object of the present invention to provide pharmaceutical compositions comprising the nucleoside compounds and derivatives thereof for use as inhibitors of RNA-dependent RNA viral polymerase and in particular as inhibitors of HCV NS5B polymerase.
It is another object of the present invention to provide pharmaceutical compositions comprising the nucleoside compounds and derivatives thereof for use as inhibitors of RNA-dependent RNA viral replication and in particular as inhibitors of HCV replication.
It is another object of the present invention to provide pharmaceutical compositions comprising the nucleoside compounds and derivatives thereof for use in the treatment of RNA-dependent RNA viral infection and in particular in the treatment of HCV infection.
It is another object of the present invention to provide pharmaceutical compositions comprising the nucleoside compounds and derivatives thereof in combination with other agents active against an RNA-dependent RNA virus and in particular against HCV.
It is another object of the present invention to provide methods for the inhibition of RNA-dependent RNA viral polymerase and in particular for the inhibition of HCV NS5B polymerase.
It is another object of the present invention to provide methods for the inhibition of RNA-dependent RNA viral replication and in particular for the inhibition of HCV replication.
It is another object of the present invention to provide methods for the treatment of RNA-dependent RNA viral infection and in particular for the treatment of HCV infection.
It is another object of the present invention to provide methods for the treatment of RNA-dependent RNA viral infection in combination with other agents active against RNA-dependent RNA virus and in particular for the treatment of HCV infection in combination with other agents active against HCV.
It is another object of the present invention to provide nucleoside compounds and certain derivatives thereof and their pharmaceutical compositions for use as a medicament for the inhibition of RNA-dependent RNA viral replication and/or the treatment of RNA-dependent RNA viral infection and in particular for the inhibition of HCV replication and/or the treatment of HCV infection.
It is another object of the present invention to provide for the use of the nucleoside compounds and certain derivatives thereof of the present invention and their pharmaceutical compositions for the manufacture of a medicament for the inhibition of RNA-dependent RNA viral replication and/or the treatment of RNA-dependent RNA viral infection and in particular for the inhibition of HCV replication and/or the treatment of HCV infection.
These and other objects will become readily apparent from the detailed description which follows.
The present invention provides a method for inhibiting RNA-dependent RNA viral polymerase, a method for inhibiting RNA-dependent RNA viral replication, and/or a method for treating RNA-dependent viral infection in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of structural formula I which is of the stereochemical configuration: 
or a pharmaceutically acceptable salt thereof;
wherein B is selected from the group consisting of 
A, G, and L are each independently CH or N;
D is N, CH, Cxe2x80x94CN, Cxe2x80x94NO2, Cxe2x80x94C1-3 alkyl, Cxe2x80x94NHCONH2, Cxe2x80x94CONR11 R11, Cxe2x80x94CSNR11R11, Cxe2x80x94COOR11, Cxe2x80x94C(xe2x95x90NH)NH2, C-hydroxy, Cxe2x80x94C1-3 alkoxy, C-amino, Cxe2x80x94C1-4 alkylamino, Cxe2x80x94di(C1-4 alkyl)amino, C-halogen, Cxe2x80x94(1,3-oxazol-2-yl), Cxe2x80x940(1,3-thiazol-2-yl), or Cxe2x80x94(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C1-3 alkoxy;
E is N or CR5;
W is O or S;
Y is H, C1-10 alkylcarbonyl, P3O9H4, P2O6H3, or P(O)R9R10;
R1 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R2 and R3 is hydroxy or C1-4 alkoxy and the other of R2 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C14 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C1-10 alkoxy, optionally substituted with C1-3 alkoxy or 1 to 3 fluorine atoms,
C2-6 alkenyloxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R2 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R1 and R3 is hydroxy or C1-4 alkoxy and the other of R1 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C1-10 alkoxy, optionally substituted with hydroxy, C1-3 alkoxy, carboxy, or 1 to 3 fluorine atoms,
C2-6 alkenyloxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC0-4 alkyl;
R4 and R6 are each independently H, OH, SH, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, halogen, C1-4 alkyl, C1-4 alkoxy, or CF3;
R5 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkylamino, CF3, or halogen;
R14 is H, CF3, C1-4 alkyl, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
R7 is hydrogen, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
each R11 is independently H or C1-6 alkyl;
R8 is H, halogen, CN, carboxy, C1-4 alkyloxycarbonyl, N3, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl;
R12 and R13 are each independently hydrogen, methyl, hydroxymethyl, or fluoromethyl; and
R9 and R10 are each independently hydroxy, OCH2CH2SC(xe2x95x90O)C1-4 alkyl, OCH2O(Cxe2x95x90O)OC1-4 alkyl, NHCHMeCO2Me, OCH(C1-4 alkyl)O(Cxe2x95x90O)C1-4 alkyl, 
with the provisos that (a) when R1 is hydrogen, one of R3 and R4 is hydrogen, and R2 is fluoro, then the other of R3 and R4 is not hydrogen, halogen, azido, trifluoromethyl, C1-4 alkyl, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, or C1-10 alkoxy; (b) when R1 is hydrogen, one of R3 and R4 is hydrogen, and R2 is halogen, hydroxy, C1-6 alkoxy, or C2-6 alkenyloxy, then the other of R3 and R4 is not hydrogen, fluoro, or azido; and (c) when R1 and R3 are hydrogen and R2 is hydroxy, then R4 is not hydroxy.
The present invention also provides novel compounds of structural formula IV of the indicated stereochemical configuration which are useful as inhibitors of RNA-dependent RNA viral polymerase. The compounds of formula IV are also inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection: 
wherein B is selected from the group consisting of 
A, G, and L are each independently CH or N;
D is N, CH, Cxe2x80x94CN, Cxe2x80x94NO2, Cxe2x80x94C1-3 alkyl, Cxe2x80x94NHCONH2, Cxe2x80x94CONR11R11, Cxe2x80x94CSNR11R11, Cxe2x80x94COOR11, Cxe2x80x94C(xe2x95x90NH)NH2, C-hydroxy, Cxe2x80x94C1-3 alkoxy, C-amino, Cxe2x80x94C1-4 alkylamino, Cxe2x80x94di(C1-4 alkyl)amino, C-halogen, Cxe2x80x94(1,3-oxazol-2-yl), Cxe2x80x94(1,3-thiazol-2-yl), or Cxe2x80x94(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C1-3 alkoxy;
E is N or CR5;
W is O or S;
R1 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R2 and R3 is hydroxy or C1-4 alkoxy and the other of R2 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C1-10 alkoxy, optionally substituted with C1-3 alkoxy or 1 to 3 fluorine atoms,
C2-6 alkenyloxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R2 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R1 and R3 is hydroxy or C1-4 alkoxy and the other of R1 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C1-10 alkoxy, optionally substituted with hydroxy, C1-3 alkoxy, carboxy, or 1 to 3 fluorine atoms,
C2-6 alkenyloxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC0-4 alkyl;
each R4 is independently H, OH, SH, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, halogen, C1-4 alkyl, C1-4 alkoxy, or CF3;
R4 and R6 are each independently H, OH, SH, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, halogen, C1-4 alkyl, C1-4 alkoxy, or CF3;
R5 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkylamino, CF3, or halogen;
R14 is H, CF3, C1-4 alkyl, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
R7 is hydrogen, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
each R11 is independently H or C1-6 alkyl;
R8 is H, halogen, CN, carboxy, C1-4 alkyloxycarbonyl, N3, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl;
R12 and R13 are each independently hydrogen, methyl, hydroxymethyl, or fluoromethyl; and
R9 and R10 are each independently hydroxy, OCH2CH2SC(xe2x95x90O)C1-4 alkyl, OCH2O(Cxe2x95x90O)OC1-4 alkyl, NHCHMeCO2Me, OCH(C1-4 alkyl)O(Cxe2x95x90O)C1-4 alkyl, 
provided that at least one of R9 and R10 is not hydroxy.
The present invention further provides novel compounds of structural formula XII of the indicated stereochemical configuration which are useful as inhibitors of RNA-dependent RNA viral polymerase and in particular of HCV NS5B polymerase: 
wherein Ra and Rh are each independently selected from the group consisting of hydrogen, cyano, azido, halogen, hydroxy, mercapto, amino, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, and C1-4 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C1-4 alkoxy, C1-4 alkylthio, or one to three fluorine atoms;
Rb is C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C1-4 alkoxy, C1-4 alkylthio, or one to three fluorine atoms;
Rc is hydrogen, fluorine, hydroxy, mercapto, C1-4 alkoxy, or C1-4 alkyl; or Rb and Rc together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC0-4 alkyl;
Rd is hydrogen, cyano, nitro, C1-3 alkyl, NHCONH2, CONRjRj, CSNRjRj, COORj, C(xe2x95x90NH)NH2, hydroxy, C1-3 alkoxy, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, halogen, (1,3-oxazol-2-yl), (1,3-thiazol-2-yl), or (imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C1-3 alkoxy;
Re and Rf are each independently hydrogen, hydroxy, halogen, C1-4 alkoxy, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, di(C3-6 cycloalkyl)amino, or C4-6 cycloheteroalkyl, unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, amino, C1-4 alkyl, and C1-4 alkoxy;
Rg is hydrogen, C1-4 alkyl, C2-4 alkynyl, halogen, cyano, carboxy, C1-4 alkyloxycarbonyl, azido, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, (C1-4 alkyl)0-2 aminomethyl, or C4-6 cycloheteroalkyl, unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, amino, C1-4 alkyl, and C1-4 alkoxy;
Ri is hydrogen, C1-10 alkylcarbonyl, P3O9H4, P2O6H3, or P(O)RmRn; each Rj is independently hydrogen or C1-6 alkyl;
Rk and Rl are each independently hydrogen, methyl, hydroxymethyl, or fluoromethyl; and
Rm and Rn are each independently hydroxy, OCH2CH2SC(xe2x95x90O)C1-4 alkyl, OCH2O(Cxe2x95x90O)OC1-4 alkyl, NHCHMeCO2Me, OCH(C1-4 alkyl)O(Cxe2x95x90O)C1-4 alkyl, 
with the proviso that when Ra and RC are xcex1-hydroxy, Re is amino, Rb is xcex2-methyl and Rh is hydrogen or Rh is xcex2-methyl and Rb is hydrogen, and Rf, Rg, Ri, Rk, and Rl are hydrogen, then Rd is not cyano or CONH2.
The compounds of formula XII are also inhibitors of RNA-dependent RNA viral replication and in particular of HCV replication and are useful for the treatment of RNA-dependent RNA viral infection and in particular for the treatment of HCV infection.
Also encompassed within the present invention are pharmaceutical compositions containing the compounds alone or in combination with other agents active against RNA-dependent RNA virus and in particular against HCV.
The present invention provides a method for inhibiting RNA-dependent RNA viral polymerase, a method for inhibiting RNA-dependent RNA viral replication, and/or a method for treating RNA-dependent RNA viral infection in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of structural formula I which is of the stereochemical configuration: 
or a pharmaceutically acceptable salt thereof;
wherein B is selected from the group consisting of 
A, G, and L are each independently CH or N;
D is N, CH, Cxe2x80x94CN, Cxe2x80x94NO2, Cxe2x80x94C1-3 alkyl, Cxe2x80x94NHCONH2, Cxe2x80x94CONR11R11, Cxe2x80x94CSNR11R11, Cxe2x80x94COOR11, Cxe2x80x94C(xe2x95x90NH)NH2, C-hydroxy, Cxe2x80x94C1-3 alkoxy, C-amino, Cxe2x80x94C1-4 alkylamino, Cxe2x80x94di(C1-4 alkyl)amino, C-halogen, Cxe2x80x94(1,3-oxazol-2-yl), Cxe2x80x94(1,3-thiazol-2-yl), or Cxe2x80x94(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C1-3 alkoxy;
E is N or CR5;
W is O or S;
Y is H, C1-10 alkylcarbonyl, P3O9H4, P2O6H3, or P(O)R9R10;
R1 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R2 and R3 is hydroxy or C1-4 alkoxy and the other of R2 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C1-10 alkoxy, optionally substituted with C1-3 alkoxy or 1 to 3 fluorine atoms,
C2-6 alkenyloxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R2 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R1 and R3 is hydroxy or C1-4 alkoxy and the other of R1 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C1-10 alkoxy, optionally substituted with hydroxy, C1-3 alkoxy, carboxy, or 1 to 3 fluorine atoms,
C2-6 alkenyloxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC0-4 alkyl;
R4 and R6 are each independently H, OH, SH, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, halogen, C1-4 alkyl, C1-4 alkoxy, or CF3;
R5 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkylamino, CF3, or halogen;
R14 is H, CF3, C1-4 alkyl, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
R7 is hydrogen, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
each R11 is independently H or C1-6 alkyl;
R8 is H, halogen, CN, carboxy, C1-4 alkyloxycarbonyl, N3, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl;
R12 and R13 are each independently hydrogen, methyl, hydroxymethyl, or fluoromethyl; and
R9 and R10 are each independently hydroxy, OCH2CH2SC(xe2x95x90O)C1-4 alkyl, OCH2O(Cxe2x95x90O)OC1-4 alkyl, NHCHMeCO2Me, OCH(C1-4 alkyl)O(Cxe2x95x90O)C1-4 alkyl, 
with the provisos that (a) when R1 is hydrogen, one of R3 and R4 is hydrogen, and R2 is fluoro, then the other of R3 and R4 is not hydrogen, halogen, azido, trifluoromethyl, C1-4 alkyl, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, or C1-10 alkoxy; (b) when
R1 is hydrogen, one of R3 and R4 is hydrogen, and R2 is halogen, hydroxy, C1-6 alkoxy, or C2-6 alkenyloxy, then the other of R3 and R4 is not hydrogen, fluoro, or azido; and (c) when R1 and R3 are hydrogen and R2 is hydroxy, then R4 is not hydroxy.
In one embodiment of the present invention is the method of inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent viral replication, and/or treating RNA-dependent RNA viral infection with a compound of structural formula II which is of the stereochemical configuration: 
wherein B is 
D is N, CH, Cxe2x80x94CN, Cxe2x80x94NO2, Cxe2x80x94C1-3 alkyl, Cxe2x80x94NHCONH2, Cxe2x80x94CONR11R11, Cxe2x80x94CSNR11R 11, Cxe2x80x94COOR11, C-hydroxy, Cxe2x80x94C1-3 alkoxy, C-amino, Cxe2x80x94C1-4 alkylamino, Cxe2x80x94di(C1-4 alkyl)amino, C-halogen, Cxe2x80x94(1,3-oxazol-2-yl), Cxe2x80x94(1,3-thiazol-2-yl), or Cxe2x80x94(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C1-3 alkoxy;
E is N or Cxe2x80x94R5;
W is O or S;
Y is H, C1-10 alkylcarbonyl, P3O9H4, or P(O)R9R10;
R1 is hydrogen, CF3, or C1-4 alkyl and one of R2 and R3 is OH or C1-4 alkoxy and the other of R2 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C1-3 alkyl,
trifluoromethyl,
C1-4 alkoxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R2 is hydrogen, CF3, or C1-4 alkyl and one of R1 and R3 is OH or C1-4 alkoxy and the other of R1 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
fluoro,
C1-4 alkyl,
trifluoromethyl,
C1-4 alkoxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC0-4 alkyl;
R4 and R6 are each independently H, OH, SH, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, halogen, C1-4 alkyl, C1-4 alkoxy, or CF3;
R5 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkylamino, CF3, or halogen;
R7 is hydrogen, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
each R11 is independently H or C1-6 alkyl;
R8 is H, halogen, CN, carboxy, C1-4 alkyloxycarbonyl, N3, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl; and
R9 and R10 are each independently hydroxy, OCH2CH2SC(xe2x95x90O)C1-4 alkyl, or OCH2O(Cxe2x95x90O)C1-4 alkyl;
with the provisos that (a) when R1 is hydrogen, one of R3 and R4 is hydrogen, and R2 is fluoro, then the other of R3 and R4 is not hydrogen, halogen, trifluoromethyl, C14 alkyl, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, or C1-4 alkoxy; (b) when R1 is hydrogen, one of R3 and R4 is hydrogen, and R2 is halogen, hydroxy, or C1-4 alkoxy, then the other of R3 and R4 is not hydrogen, fluoro, or azido; and (c) when R1 and R3 are hydrogen and R2 is hydroxy, then R4 is not hydroxy.
In a second embodiment of the present invention is the method of inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with a compound of structural formula III which is of the stereochemical configuration: 
wherein B is 
D is N, CH, Cxe2x80x94CN, Cxe2x80x94NO2, Cxe2x80x94C1-3 alkyl, Cxe2x80x94NHCONH2, Cxe2x80x94CONR11R 11, Cxe2x80x94CSNR11 R11, Cxe2x80x94COOR11, C-hydroxy, Cxe2x80x94C1-3 alkoxy, C-amino, Cxe2x80x94C1-4 alkylamino, Cxe2x80x94di(C1-4 alkyl)amino, C-halogen, Cxe2x80x94(1,3-oxazol-2-yl), Cxe2x80x94(1,3-thiazol-2-yl), or Cxe2x80x94(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C13 alkoxy;
W is O or S;
Y is H, C1-10 alkylcarbonyl, P3O9H4, P2O6H3, or P(O)R9R10;
R1 is hydrogen, CF3, or C1-4 alkyl and one of R2 and R3 is OH or C1-4 alkoxy and the other of R2 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
fluoro,
C1-3 alkyl,
trifluoromethyl,
C1-8 alkylcarbonyloxy,
C13 alkoxy, and
amino; or
R2 is hydrogen, CF3, or C1-4 alkyl and one of R1 and R3 is OH or C1-4 alkoxy and the other of R1 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
fluoro,
C1-3 alkyl,
trifluoromethyl,
C1-8 alkylcarbonyloxy,
C1-3 alkoxy, and
amino; or
R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC0-4 alkyl;
R6 is H, OH, SH, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, halogen, C1-4 alkyl, C1-4 alkoxy, or CF3;
R5 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkylamino, CF3, or halogen;
R7 is hydrogen, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
each R11 is independently H or C1-6 alkyl;
R8 is H, halogen, CN, carboxy, C1-4 alkyloxycarbonyl, N3, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl; and
R9 and R10 are each independently hydroxy, OCH2CH2SC(xe2x95x90O)t-butyl, or OCH2O(Cxe2x95x90O)iPr;
with the provisos that (a) when R1 is hydrogen and R2 is fluoro, then R3 is not hydrogen, trifluoromethyl, fluoro, C1-3 alkyl, amino, or C1-3 alkoxy; (b) when R1 is hydrogen and R2 is fluoro, hydroxy, or C1-3 alkoxy, then R3 is not hydrogen or fluoro; and (c) when R1 is hydrogen and R2 is hydroxy, then R3 is not xcex2-hydroxy.
In a class of this embodiment is the method of inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with a compound of structural formula III wherein B is 
and W, Y, and the R substituents are as defined under this second embodiment.
In a second class of this embodiment is the method of inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection with a compound of structural formula m wherein B is 
and Y, D, and the R substituents are as defined under this second embodiment.
In a third embodiment of the present invention, the RNA-dependent RNA viral polymerase is a positive-sense single-stranded RNA-dependent RNA viral polymerase. In a class of this embodiment, the positive-sense single-stranded RNA-dependent RNA viral polymerase is a Flaviviridae viral polymerase or a Picornaviridae viral polymerase. In a subclass of this class, the Picornaviridae viral polymerase is rhinovirus polymerase, poliovirus polymerase, or hepatitis A virus polymerase. In a second subclass of this class, the Flaviviridae viral polymerase is selected from the group consisting of hepatitis C virus polymerase, yellow fever virus polymerase, dengue virus polymerase, West Nile virus polymerase, Japanese encephalitis virus polymerase, Banzi virus polymerase, and bovine viral diarrhea virus (BVDV) polymerase. In a subclass of this subclass, the Flaviviridae viral polymerase is hepatitis C virus polymerase.
In a fourth embodiment of the present invention, the RNA-dependent RNA viral replication is a positive-sense single-stranded RNA-dependent RNA viral replication. In a class of this embodiment, the positive-sense single-stranded RNA-dependent RNA viral replication is Flaviviridae viral replication or Picornaviridae viral replication. In a subclass of this class, the Picomnaviridae viral replication is rhinovirus replication, poliovirus replication, or hepatitis A virus replication. In a second subclass of this class, the Flaviviridae viral replication is selected from the group consisting of hepatitis C virus replication, yellow fever virus replication, dengue virus replication, West Nile virus replication, Japanese encephalitis virus replication, Banzi virus replication, and bovine viral diarrhea virus replication. In a subclass of this subclass, the Flaviviridae viral replication is hepatitis C virus replication.
In a fifth embodiment of the present invention, the RNA-dependent RNA viral infection is a positive-sense single-stranded RNA-dependent viral infection. In a class of this embodiment, the positive-sense single-stranded RNA-dependent RNA viral infection is Flaviviridae viral infection or Picornaviridae viral infection. In a subclass of this class, the Picomnaviridae viral infection is rhinovirus infection, poliovirus infection, or hepatitis A virus infection. In a second subclass of this class, the Flaviviridae viral infection is selected from the group consisting of hepatitis C virus infection, yellow fever virus infection, dengue virus infection, West Nile virus infection, Japanese encephalitis virus infection, Banzi virus infection, and bovine viral diarrhea virus infection. In a subclass of this subclass, the Flaviviridae viral infection is hepatitis C virus infection.
Illustrative of the invention is a method for inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection wherein the compound is selected from:
2xe2x80x2-O-methyl-cytidine,
2xe2x80x2-C-methyl-cytidine,
3xe2x80x2,5xe2x80x2-di-O-octanoyl-2xe2x80x2-O-methyl-cytidine,
3xe2x80x2-O-octanoyl-2xe2x80x2-O-methyl-cytidine,
2xe2x80x2-C-methyl-adenosine,
8-amino-2xe2x80x2-C-methyladenosine,
4-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile,
4-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide,
3xe2x80x2-deoxy-3xe2x80x2-methyl-cytidine,
4-amino-7-(3-deoxy-3-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
3xe2x80x2-deoxy-adenosine,
4-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
3xe2x80x2-amino-3xe2x80x2-deoxyadenosine,
2-amino-3,4-dihydro-4-oxo-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
4-amino-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
2-amino-3,4-dihydro-4-oxo-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
2-amino-5-ethyl-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
6-amino-1-(xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
3xe2x80x2-deoxyguanosine,
2-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2xe2x80x2-O-methylguanosine,
2-amino-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(2-O-methyl-xcex2-D-ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one,
7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
3xe2x80x2-deoxycytidine,
2-amino-5-methyl-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-3,4-dihydro-4-oxo-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidin-5-carbonitrile,
2-amino-5-methyl-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
8-azidoguanosine,
8-aminoguanosine,
8-bromoadenosine,
8-aminoadenosine,
8-bromoguanosine,
3xe2x80x2-deoxy-3xe2x80x2-fluorocytidine,
3xe2x80x2-deoxy-3xe2x80x2-fluoroguanosine,
4-amino-7-(3-deoxy-3-fluoro-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
2-amino-4-chloro-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
2-amino-4-chloro-5-ethyl-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-4-chloro-5-methyl-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidine,
2-amino-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-thione,
2-amino-4-chloro-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]
2-amino-7-(P-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-4-chloro-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-4-chloro-5-methyl-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
1-(xcex2-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidin-4(3H)-one,
4-amino-1-(xcex2-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,
2-amino-6-chloro-9-(xcex2-D-ribofuranosyl)-9H-purine,
2-amino-4-chloro-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
6-methyl-9-(xcex2-D-ribofuranosyl)-9H-purine,
2-amino-7-(2-deoxy-2-fluoro-xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-4-chloro-7-(2-deoxy-2-fluoro-xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-7-(xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(xcex2-D-arabinofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
2-amino-5-methyl-7-(xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
9-(xcex2-D-arabinofuranosyl)-9H-purin-6(1H)-one,
1-(xcex2-D-arabinofuranosyl)-1 H-cytosine,
2-amino-4-chloro-5-methyl-7-(xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
3xe2x80x2-deoxy-3xe2x80x2-(fluoromethyl)-guanosine,
2xe2x80x2-amino-2xe2x80x2-deoxycytidine,
4-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
2xe2x80x2-O-methyladenosine,
4-amino-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
3xe2x80x2-amino-3xe2x80x2-deoxy-2xe2x80x2-O-methyl-adenosine,
3xe2x80x2-deoxy-3xe2x80x2-methyl-uridine,
6-amino-1-(3-deoxy-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
6-amino-1-(3-deoxy-3-fluoro-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(3H)-one,
3xe2x80x2-deoxy-3xe2x80x2-fluorouridine,
3xe2x80x2-deoxy-3xe2x80x2-fluoroadenosine,
2-amino-7-(2-deoxy-xcex2-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
3xe2x80x2-deoxy-5-methyl-uridine,
3xe2x80x2-deoxy-2xe2x80x2-O-(2-methoxyethyl)-3xe2x80x2-methyl-5-methyluridine,
2xe2x80x2-amino-2xe2x80x2-deoxy-uridine,
2-amino-9-(xcex2-D-arabinofuranosyl)-9H-purin-6(1H)-one,
3xe2x80x2-deoxy-3xe2x80x2-methylguanosine,
2xe2x80x2-O-[4-(imidazolyl-1)butyl]guanosine,
2xe2x80x2-deoxy-2xe2x80x2-fluoroguanosine,
2xe2x80x2-deoxyguanosine,
2-amino-7-(2-deoxy-2-fluoro-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
2-amino-5-iodo-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(3-deoxy-3-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
2-amino-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(2-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(3-deoxy-3-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(3-deoxy-3-fluoro-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
6-amino-1-(2-O-methyl-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
6-amino-1-(2-deoxy-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
6-amino-1-(3-deoxy-3-methyl-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
6-amino-1-(2-deoxy-2-fluoro-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
6-amino-1-(xcex2-D-arabinofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
2xe2x80x2-O-[2-(N,N-diethylaminooxy)ethyl]-5-methyluridine,
5-ethynyl-2xe2x80x2-O-(2-methoxyethyl)-cytidine,
1-(2-C-methyl-xcex2-D-arabinofuranosyl)uracil,
5-methyl-3xe2x80x2-deoxycytidine,
2-amino-2xe2x80x2-O-methyladenosine,
2xe2x80x2-deoxy-2xe2x80x2-fluoroadenosine,
3xe2x80x2-deoxy-3xe2x80x2-fluoroadenosine,
3xe2x80x2-deoxy-3xe2x80x2-methyladenosine,
2-amino-7-(2-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(3-deoxy-3-fluoro-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
4-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
4-amino-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-1-(3-deoxy-3-fluoro-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,
4-amino-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (tubercidin),
4,6-diamino-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-7-(3-deoxy-3-fluoro-xcex2-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidin-5-carboxamide,
4-amino-1-(3-deoxy-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,
4-amino-1-(3-deoxy-3-methyl-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,
4-amino-1-(xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,
4-amino-1-(2-C-methyl-xcex2-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-amino-7-(3-deoxy-3-fluoro-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine; and
the corresponding 5xe2x80x2-triphosphates, 5xe2x80x2-[bis(isopropyloxycarbonyloxymethyl)]monophosphates, 5xe2x80x2-mono-(S-C1-4 
alkanoyl-2-thioethyl)monophosphates, and 5xe2x80x2-bis-(S-C1-4 alkanoyl-2-thioethyl) monophosphates thereof;
or a pharmaceutically acceptable salt thereof.
Further illustrative of the invention is a method for inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection wherein the compound is selected from:
2xe2x80x2-O-methyl-cytidine,
2xe2x80x2-C-methyl-cytidine,
3xe2x80x2,5xe2x80x2-di-O-octanoyl-2xe2x80x2-O-methyl-cytidine,
3xe2x80x2-O-octanoyl-2xe2x80x2-O-methyl-cytidine,
4-amino-1-(xcex2-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile,
4-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide,
2xe2x80x2-C-methyladenosine,
8-amino-2xe2x80x2-C-methyladenosine,
3xe2x80x2-deoxy-3xe2x80x2-methyl-cytidine,
4-amino-7-(3-deoxy-3-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
3xe2x80x2-deoxyadenosine,
4-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
3xe2x80x2-amino-3xe2x80x2-deoxyadenosine,
2-amino-3,4-dihydro-4-oxo-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
4-amino-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
2-amino-3,4-dihydro-4-oxo-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
2-amino-5-ethyl-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
6-amino-1-(xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
3xe2x80x2-deoxyguanosine,
2-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2xe2x80x2-O-methylguanosine,
2-amino-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(2-O-methyl-xcex2-D-ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidin-4-(3H)-one,
7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
3xe2x80x2-deoxy-cytidine,
2-amino-5-methyl-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-3,4-dihydro-4-oxo-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidine-5-carbonitrile,
2-amino-5-methyl-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
8-azidoguanosine,
8-aminoguanosine,
8-bromoadenosine,
8-aminoadenosine,
8-bromoguanosine,
3xe2x80x2-deoxy-3xe2x80x2-fluorocytidine,
3xe2x80x2-deoxy-3xe2x80x2-fluoroguanosine,
4-amino-7-(3-deoxy-3-fluoro-xe2x80x94-D-ribofuranosyl)-7H-pyrrolo[2,3-d]-pyrimidin-5-carboxamide,
2-amino-4-chloro-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
2-amino-4-chloro-5-ethyl-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-4-chloro-5-methyl-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidine,
2-amino-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-4-chloro-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-4-chloro-5-methyl-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-7-(2-deoxy-2-fluoro-xcex2-D-arabinofuranosyl)-7H-pyrrolo [2,3-d]pyrimidin-4(3H)-one,
4-amino-1-(2-C-methyl-xcex2-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,
2-amino-7-(xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one, and
2-amino-7-(xcex2-D-arabinofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile; and
the corresponding 5xe2x80x2-triphosphates, 5xe2x80x2-[bis(isopropyloxycarbonyloxymethyl)]monophosphates, 5xe2x80x2-mono-(S-pivaloyl-2-thioethyl) monophosphates, and 5xe2x80x2-bis-(S-pivaloyl-2-thioethyl) monophosphates thereof;
or a pharmaceutically acceptable salt thereof.
Even further illustrative of the present invention is a method for inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection wherein the compound is selected from
2xe2x80x2-O-methyl-cytidine,
2xe2x80x2-C-methyl-cytidine,
3xe2x80x2,5xe2x80x2-di-O-octanoyl-2xe2x80x2-O-methyl-cytidine,
3xe2x80x2-O-octanoyl-2xe2x80x2-O-methyl-cytidine,
4-amino-1-(xcex2-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile,
4-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide,
2xe2x80x2-C-methyladenosine,
8-amino-2xe2x80x2-C-methyladenosine,
8-bromoguanosine,
8-aminoguanosine,
8-aminoadenosine,
4-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-4-chloro-5-ethyl-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-3,4-dihydro-4-oxo-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
4-amino-1-(2-C-methyl-xcex2-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,
2-amino-4-chloro-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo [2,3-d]pyrimidin-5-carbonitrile;
and the corresponding 5xe2x80x2-triphosphates thereof;
2xe2x80x2-O-methylcytidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate],
2-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate],
3xe2x80x2-deoxyguanosine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate], and
3xe2x80x2-deoxycytidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate];
or a pharmaceutically acceptable salt thereof.
Yet further illustrative of the invention is a method for inhibiting RNA-dependent RNA viral polymerase, inhibiting RNA-dependent RNA viral replication, and/or treating RNA-dependent RNA viral infection wherein the compound is selected from:
2xe2x80x2-O-methylcytidine,
2xe2x80x2-C-methylcytidine,
3xe2x80x2,5xe2x80x2-di-O-octanoyl-2xe2x80x2-O-methyl-cytidine,
3xe2x80x2-O-octanoyl-2xe2x80x2-O-methyl-cytidine,
4-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile,
4-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide,
2xe2x80x2-C-methyladenosine,
8-amino-2xe2x80x2-C-methyladenosine,
2xe2x80x2-O-methylcytidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate],
2-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo [2,3-d]pyrimidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate], and 3xe2x80x2-deoxycytidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate];
or a pharmaceutically acceptable salt thereof.
The present invention also provides novel compounds of structural formula IV of the indicated stereochemical configuration which are useful as inhibitors of RNA-dependent RNA viral polymerase: 
wherein B is selected from the group consisting of 
A, G, and L are each independently CH or N;
D is N, CH, Cxe2x80x94CN, Cxe2x80x94NO2, Cxe2x80x94C1-3 alkyl, Cxe2x80x94NHCONH2, Cxe2x80x94CONR11R11, Cxe2x80x94CSNR11R11, Cxe2x80x94COOR11, C-hydroxy, Cxe2x80x94C1-3 alkoxy, C-amino, Cxe2x80x94C1-4 alkylamino, Cxe2x80x94di(C1-4 alkyl)amino, C-halogen, Cxe2x80x94(1,3-oxazol-2-yl), Cxe2x80x94(1,3-thiazol-2-yl), or Cxe2x80x94(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C1-3 alkoxy;
E is N or CR5;
W is O or S;
R1 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R2 and R3 is hydroxy or C1-4 alkoxy and the other of R2 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C14 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C1xe2x80x83alkoxy, optionally substituted with C1-3 alkoxy or 1 to 3 fluorine
atoms,
C2-6 alkenyloxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R2 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R1 and R3 is hydroxy or C1-4 alkoxy and the other of R1 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C1-4 alkyl, optionally substituted with 1 to 3 fluorine atoms,
C1-10 alkoxy, optionally substituted with hydroxy, C1-3 alkoxy, carboxy, or 1 to 3 fluorine atoms,
C2-6 alkenyloxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC0-4 alkyl;
R4 and R6 are each independently H, OH, SH, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, halogen, C1-4 alkyl, C1-4 alkoxy, or CF3;
R5 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkylamino, CF3, or halogen
R14 is H, CF3, C1-4 alkyl, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
R7 is hydrogen, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
each R11 is independently H or C1-6 alkyl;
R8 is H, halogen, CN, carboxy, C1-4 alkyloxycarbonyl, N3, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl;
R12 and R13 are each independently hydrogen or methyl; and
R9 and R10 are each independently hydroxy, OCH2CH2SC(xe2x95x90O)C1-4 alkyl, OCH2O(Cxe2x95x90O)OC1-4 alkyl, NHCHMeCO2Me, OCH(C1-4 alkyl)O(Cxe2x95x90O)C1-4 alkyl, 
provided that at least one of R9 and R10 is not hydroxy.
The compounds of formula IV are also inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection.
In one embodiment, there are provided novel compounds of structural formula V which are of the stereochemical configuration: 
wherein B is 
D is N, CH, Cxe2x80x94CN, Cxe2x80x94NO2, Cxe2x80x94C1-3 alkyl, Cxe2x80x94NHCONH2, Cxe2x80x94CONR11R11, Cxe2x80x94CSNR11R11, Cxe2x80x94COOR11, C-hydroxy, Cxe2x80x94C1-3 alkoxy, C-amino, Cxe2x80x94C1-4 alkylamino, Cxe2x80x94di(C1-4 alkyl)amino, C-halogen, Cxe2x80x94(1,3-oxazol-2-yl), Cxe2x80x94(1,3-thiazol-2-yl), or Cxe2x80x94(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C1-3 alkoxy;
W is O or S;
E is N or C-R5;
R1 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R2 and R3 is hydroxy or C1-4 alkoxy and the other of R2 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
halogen,
C1-3 alkyl,
trifluoromethyl,
C1-4 alkoxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
aryloxycarbonyl,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R2 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R1 and R3 is hydroxy or C1-4 alkoxy and the other of R1 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
fluoro,
C1-4 alkyl,
trifluoromethyl,
C1-4 alkoxy,
C1-4 alkylthio,
C1-8 alkylcarbonyloxy,
azido,
amino,
C1-4 alkylamino, and
di(C1-4 alkyl)amino; or
R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC0-4 alkyl;
R4 and R6 are each independently H, OH, SH, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, halogen, C1-4 alkyl, C1-4 alkoxy, or CF3;
R5 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkylamino, CF3, or halogen;
R7 is hydrogen, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
each R11 is independently H or C1-6 alkyl;
R8 is H, halogen, CN, carboxy, C1-4 alkyloxycarbonyl, N3, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl; and
R9 and R10 are each independently hydroxy, OCH2CH2SC(xe2x95x90O)C1-4 alkyl, or OCH2O(Cxe2x95x90O)C1-4 alkyl, provided that at least one of R9 and R10 is not hydroxy.
In a second embodiment, there are provided novel compounds of structural formula VI: 
wherein B is 
D is N, CH, Cxe2x80x94CN, Cxe2x80x94NO2, Cxe2x80x94C1-3 alkyl, Cxe2x80x94NHCONH2, Cxe2x80x94CONR11R11, Cxe2x80x94CSNR11R11, Cxe2x80x94COOR11, C-hydroxy, Cxe2x80x94C1-3 alkoxy, C-amino, Cxe2x80x94C1-4 alkylamino, Cxe2x80x94di(C1-4 alkyl)amino, C-halogen, Cxe2x80x94(1,3-oxazol-2-yl), Cxe2x80x94(1,3-thiazol-2-yl), or Cxe2x80x94(imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C1-3 alkoxy;
W is O or S;
R1 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R2 and R3 is hydroxy or C1-4 alkoxy and the other of R2 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
fluoro,
C1-3 alkyl,
trifluoromethyl,
C1-3 alkoxy,
C1-8 alkylcarbonyloxy, and
amino; or
R2 is hydrogen, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl optionally substituted with amino, hydroxy, or 1 to 3 fluorine atoms and one of R1 and R3 is hydroxy or C1-4 alkoxy and the other of R1 and R3 is selected from the group consisting of
hydrogen,
hydroxy,
fluoro,
C1-3 alkyl,
trifluoromethyl,
C1-3 alkoxy,
C1-8 alkylcarbonyloxy, and
amino; or
R1 and R2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC0-4 alkyl;
R6 is H, OH, SH, NH2, C1-4 alkylamino, di(C1-4 alkyl)amino,
C3-6 cycloalkylamino, halogen, C1-4 alkyl, C1-4 alkoxy, or CF3;
R5 is H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 alkylamino, CF3, or halogen;
R7 is hydrogen, amino, C1-4 alkylamino, C3-6 cycloalkylamino, or di(C1-4 alkyl)amino;
each R11 is independently H or C1-6 alkyl;
R8 is H, halogen, CN, carboxy, C1-4 alkyloxycarbonyl, N3, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, or (C1-4 alkyl)0-2 aminomethyl; and
R9 and R10 are each independently hydroxy, OCH2CH2SC(xe2x95x90O)t-butyl, or OCH2O(Cxe2x95x90O)iPr, provided that at least one of R9 and R10 is not hydroxy.
Illustrative of the novel compounds of structural formula VI of the present invention are the following:
2xe2x80x2-O-methylcytidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate],
2-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate],
3xe2x80x2-deoxyguanosine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate],
2xe2x80x2-O-methylguanosine-5xe2x80x2-[bis-(S-acetyl-2-thioethyl)phosphate],
2xe2x80x2-O-methylguanosine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate],
8-bromo-2xe2x80x2-O-methylguanosine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate],
2-amino-3,4-dihydro-7-(2-O-methyl-xcex2-D-ribofuranosyl)-4-oxo-7H-pyrrolo [2,3-d]pyrimidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate],
2-amino-5-bromo-7-(3-deoxy-xcex2-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo [2,3-d]pyrimidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate],
5-bromo-2xe2x80x2-O-methylcytidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate],
3xe2x80x2-deoxycytidine-5xe2x80x2-[bis-(S-pivaloyl-2-thioethyl)phosphate], and
2xe2x80x2-O-methylcytidine-5xe2x80x2-[bis(isopropyloxycarbonyloxymethyl)]phosphate.
The present invention further provides novel compounds of structural formula XII of the indicated stereochemical configuration or a pharmaceutically acceptable salt thereof which are useful as inhibitors of RNA-dependent RNA viral polymerase: 
wherein Ra and Rh are each independently selected from the group consisting of hydrogen, cyano, azido, halogen, hydroxy, mercapto, amino, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl, and C1-4 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C1-4 alkoxy, C1-4 alkylthio, or one to three fluorine atoms;
Rb is C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C1-4 alkoxy, C1-4 alkylthio, or one to three fluorine atoms;
Rc is hydrogen, fluorine, hydroxy, mercapto, C1-4 alkoxy, or C1-4 alkyl; or Rb and Rc together with the carbon atom to which they are attached form a 3- to 6-membered saturated monocyclic ring system optionally containing a heteroatom selected from O, S, and NC0-4 alkyl;
Rd is hydrogen, cyano, nitro, C1-3 alkyl, NHCONH2, CONRjRj, CSNRjRj, COORj, C(xe2x95x90NH)NH2, hydroxy, C1-3 alkoxy, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, halogen, (1,3-oxazol-2-yl), (1,3-thiazol-2-yl), or (imidazol-2-yl); wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, amino, hydroxy, carboxy, and C1-3 alkoxy;
Re and Rf are each independently hydrogen, hydroxy, halogen, C1-4 alkoxy, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, C3-6 cycloalkylamino, di(C3-6 cycloalkyl)amino, or C4-6 cycloheteroalkyl, unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, amino, C1-4 alkyl, and C1-4 alkoxy;
Rg is hydrogen, C1-4 alkyl, C2-4 alkynyl, halogen, cyano, carboxy, C1-4 alkyloxycarbonyl, azido, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, (C1-4 alkyl)0-2 aminomethyl, or C4-6 cycloheteroalkyl, unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, amino, C1-4 alkyl, and C1-4 alkoxy;
Ri is hydrogen, C1-10 alkylcarbonyl, P3O9H4, P2O6H3, or P(O)RmRn;
each Rj is independently hydrogen or C1-6 alkyl;
Rk and Rl are each independently hydrogen, methyl, hydroxymethyl, or fluoromethyl; and
Rm and Rn are each independently hydroxy, OCH2CH2SC(xe2x95x90O)C1-4 alkyl, OCH2O(Cxe2x95x90O)OC1-4 alkyl, NHCHMeCO2Me, OCH(C1-4 alkyl)O(Cxe2x95x90O)C1-4 alkyl, 
with the proviso that when Ra and Rc are xcex1-hydroxy, Re is amino, Rb is xcex2-methyl and Rh is hydrogen or Rh is xcex2-methyl and Rb is hydrogen, and Rf, Rg, Ri, Rk, and Rl are hydrogen, then Rd is not cyano or CONH2.
The compounds of formula XII are also inhibitors of RNA-dependent RNA viral replication and are useful for the treatment of RNA-dependent RNA viral infection.
In one embodiment of the novel compounds of structural formula XII are the compounds of structural formula XIII: 
wherein Ra is hydrogen, halogen, hydroxy, amino, or C1-3 alkoxy;
Rb is C1-3 alkyl, wherein alkyl is unsubstituted or substituted with hydroxy, amino, C1-3 alkoxy, C1-3 alkylthio, or one to three fluorine atoms;
Rc is hydroxy, fluoro, or C1-4 alkoxy;
Rd is hydrogen, cyano, methyl, halogen, or CONH2;
Rg is hydrogen, amino, or C1-4 alkylamino;
Ri is hydrogen, P3O9H4, P2O6H3, or PO3H2; and
Re and Rf are each independently hydrogen, hydroxy, halogen, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, or C3-6 cycloalkylamino;
with the proviso that when Ra and Rc are xcex1-hydroxy, Re is amino, Rb is methyl, and Rf, Rg, and Ri are hydrogen, then Rd is not cyano or CONH2.
In a second embodiment of the compounds of structural formula XII are the compounds of structural formula XII wherein:
Rb is methyl, fluoromethyl, hydroxymethyl, difluoromethyl, trifluoromethyl, or aminomethyl;
Rc is hydroxy, fluoro, or methoxy;
Ra is hydrogen, fluoro, hydroxy, amino, or methoxy;
Ri is hydrogen or P3O9H4;
Rg is hydrogen or amino;
Rd is hydrogen, cyano, methyl, halogen, or CONH2; and
Re and Rf are each independently hydrogen, fluoro, hydroxy, or amino;
with the proviso that when Rb is xcex2-methyl, Ra and Rc are xcex1-hydroxy, Re is amino, and Rf, Rg, and Ri are hydrogen, then Rd is not cyano or CONH2.
Illustrative of the novel compounds of the present invention of structural formula XIII which are useful as inhibitors of RNA-dependent RNA viral polymerase are the following:
4-amino-7-(2-C-methyl-xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-methylamino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-dimethylamino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-cyclopropylamino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-vinyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-hydroxymethyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-fluoromethyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-methyl-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid,
4-amino-5-bromo-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-chloro-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-fluoro-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2,4-diamino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-4-cyclopropylamino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
4-amino-7-(2-C-ethyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C,2-O-dimethyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-5-methyl-7-(2-C, 2-O-dimethyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
4-amino-7-(3-deoxy-2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(3-deoxy-2-C-methyl-xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]-pyrimidine
4-amino-2-fluoro-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(3-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(3-C-methyl-xcex2-D-xylofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2,4-di-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, and
4-amino-7-(3-deoxy-3-fluoro-2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine;
and the corresponding 5xe2x80x2-triphosphates;
or a pharmaceutically acceptable salt thereof.
Further illustrative of the novel compounds of the present invention of structural formula XIII which are useful as inhibitors of RNA-dependent RNA viral polymerase are the following:
4-amino-7-(2-C-methyl-xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-7-(2-C-fluoromethyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-methyl-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-bromo-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-chloro-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
4-amino-5-fluoro-7-(2-C-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, and
4-amino-7-(2-C,2-O-dimethyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, and the corresponding 5xe2x80x2-triphosphates;
or a pharmaceutically acceptable salt thereof.
Further structurally novel nucleoside derivatives of the present invention which are useful as inhibitors of RNA-dependent RNA viral polymerase are the following:
3xe2x80x2-deoxy-3xe2x80x2-methyl-cytidine,
3xe2x80x2,5xe2x80x2-di-O-octanoyl-2xe2x80x2-O-methyl-cytidine,
3xe2x80x2-O-octanoyl-2xe2x80x2-O-methyl-cytidine,
4-amino-7-(3-deoxy-3-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carboxamide,
2-amino-5-ethyl-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(2-O-methyl-xcex2-D-ribofuranosyl)-5H-pyrrolo[3,2-d]pyrimidin-4(3H)-one,
7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-3,4-dihydro-4-oxo-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidin-5-carbonitrile,
2-amino-5-methyl-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-4-chloro-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile
2-amino-4-chloro-5-ethyl-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-4-chloro-5-methyl-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo [2,3-d]pyrimidine,
2-amino-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo [2,3-d]pyrimidin-4(3H)-thione,
2-amino-4-chloro-7-(2-O-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-4-chloro-5-methyl-7-(xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-7-(2-deoxy-2-fluoro-xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-4-chloro-7-(2-deoxy-2-fluoro-xcex2-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine,
2-amino-7-(xcex2-D-arabinofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
9-(xcex2-D-arabinofuranosyl)-9H-purin-6(1H)-one,
3xe2x80x2-amino-3xe2x80x2-deoxy-2xe2x80x2-O-methyl-adenosine,
8-amino-2xe2x80x2-C-methyladenosine,
6-amino-1-(3-deoxy-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
6-amino-1-(3-deoxy-3-fluoro-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(3H)-one,
3xe2x80x2-deoxy-2xe2x80x2-O-(2-methoxyethyl)-3xe2x80x2-methyl-5-methyluridine,
2-amino-7-(3-deoxy-xcex2-D-ribofuranosyl)-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
2-amino-7-(3-deoxy-3-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-5-carbonitrile,
2-amino-7-(3-deoxy-3-methyl-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
2-amino-7-(3-deoxy-3-fluoro-xcex2-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one,
6-amino-1-(2-O-methyl-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
6-amino-1-(3-deoxy-3-methyl-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
6-amino-1-(2-deoxy-2-fluoro-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridin-4(5H)-one,
1-(2-C-methyl-xcex2-D-arabinofuranosyl)uracil,
4-amino-1-(3-deoxy-3-fluoro-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine,
2-amino-7-(-3-deoxy-3-fluoro-xcex2-D-ribofuranosyl)-7H-pyrrolo-[2,3-d]pyrimidin-5-carboxamide,
4-amino-1-(2-C-methyl-xcex2-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine,
4-amino-1-(3-deoxy-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine, and
4-amino-1-(3-deoxy-3-methyl-xcex2-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine;
and the corresponding 5xe2x80x2-triphosphates;
or a pharmaceutically acceptable salt thereof.
In a further embodiment the novel compounds of the present invention are useful as inhibitors of positive-sense single-stranded RNA-dependent RNA viral polymerase, inhibitors of positive-sense single-stranded RNA-dependent RNA viral replication, and/or for the treatment of positive-sense single-stranded RNA-dependent RNA viral infection. In a class of this embodiment, the positive-sense single-stranded RNA-dependent RNA virus is a Flaviviridae virus or a Picornaviridae virus. In a subclass of this class, the Picornaviridae virus is a rhinovirus, a poliovirus, or a hepatitis A virus. In a second subclass of this class, the Flaviviridae virus is selected from the group consisting of hepatitis C virus, yellow fever virus, dengue virus, West Nile virus, Japanese encephalitis virus, Banzi virus, and bovine viral diarrhea virus (BVDV). In a subclass of this subclass, the Flaviviridae virus is hepatitis C virus.
Throughout the instant application, the following terms have the indicated meanings:
The alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The term xe2x80x9calkenylxe2x80x9d shall mean straight or branched chain alkenes of two to six total carbon atoms, or any number within this range (e.g., ethenyl, propenyl, butenyl, pentenyl, etc.).
The term xe2x80x9calkynylxe2x80x9d shall mean straight or branched chain alkynes of two to six total carbon atoms, or any number within this range (e.g., ethynyl, propynyl, butynyl, pentynyl, etc.).
The term xe2x80x9ccycloalkylxe2x80x9d shall mean cyclic rings of alkanes of three to eight total carbon atoms, or any number within this range (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).
The term xe2x80x9ccycloheteroalkylxe2x80x9d is intended to include non-aromatic heterocycles containing one or two heteroatoms selected from nitrogen, oxygen and sulfur. Examples of 4-6-membered cycloheteroalkyl include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, piperazinyl, and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to straight or branched chain alkoxides of the number of carbon atoms specified (e.g., C1-4 alkoxy), or any number within this range [i.e., methoxy (MeOxe2x80x94), ethoxy, isopropoxy, etc.].
The term xe2x80x9calkylthioxe2x80x9d refers to straight or branched chain alkylsulfides of the number of carbon atoms specified (e.g., C1-4 alkylthio), or any number within this range [i.e., methylthio (MeSxe2x80x94), ethylthio, isopropylthio, etc.].
The term xe2x80x9calkylaminoxe2x80x9d refers to straight or branched alkylamines of the number of carbon atoms specified (e.g., C1-4 alkylamino), or any number within this range [i.e., methylamino, ethylamino, isopropylamino, t-butylamino, etc.].
The term xe2x80x9calkylsulfonylxe2x80x9d refers to straight or branched chain alkylsulfones of the number of carbon atoms specified (e.g., C1-6 alkylsulfonyl), or any number within this range [i.e., methylsulfonyl (MeSO2xe2x80x94), ethylsulfonyl, isopropylsulfonyl, etc.].
The term xe2x80x9calkyloxycarbonylxe2x80x9d refers to straight or branched chain esters of a carboxylic acid derivative of the present invention of the number of carbon atoms specified (e.g., C1-4 alkyloxycarbonyl), or any number within this range [i.e., methyloxycarbonyl (MeOCOxe2x80x94), ethyloxycarbonyl, or butyloxycarbonyl].
The term xe2x80x9carylxe2x80x9d includes both phenyl, naphthyl, and pyridyl. The aryl group is optionally substituted with one to three groups independently selected from C1-4 alkyl, halogen, cyano, nitro, trifluoromethyl, C1-4 alkoxy, and C1-4 alkylthio.
The term xe2x80x9chalogenxe2x80x9d is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
The term xe2x80x9csubstitutedxe2x80x9d shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
The term xe2x80x9c5xe2x80x2-triphosphatexe2x80x9d refers to a triphosphoric acid ester derivative of the 5xe2x80x2-hydroxyl group of a nucleoside compound of the present invention having the following general structural formula VII: 
wherein B, Z, R1-R4, R12, and R13 are as defined above. The compounds of the present invention are also intended to include pharmaceutically acceptable salts of the triphosphate ester as well as pharmaceutically acceptable salts of 5xe2x80x2-monophosphate and 5xe2x80x2-diphosphate ester derivatives of the structural formulae VIII and IX, respectively, 
The term xe2x80x9c5xe2x80x2-(S-acyl-2-thioethyl)phosphatexe2x80x9d or xe2x80x9cSATExe2x80x9d refers to a mono- or di-ester derivative of a 5xe2x80x2-monophosphate nucleoside of the present invention of structural formulae X and XI, respectively, as well as pharmaceutically acceptable salts of the mono-ester, 
The term xe2x80x9ccompositionxe2x80x9d, as in xe2x80x9cpharmaceutical composition,xe2x80x9d is intended to encompass a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
The terms xe2x80x9cadministration ofxe2x80x9d and xe2x80x9cadministering axe2x80x9d compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need.
Another aspect of the present invention is concerned with a method of inhibiting HCV NS5B polymerase, inhibiting HCV replication, or treating HCV infection with a compound of the present invention in combination with one or more agents useful for treating HCV infection. Such agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha-1, interferon-xcex1, pegylated interferon-xcex1 (peginterferon-xcex1), a combination of interferon-xcex1 and ribavirin, a combination of peginterferon-xcex1 and ribavirin, a combination of interferon-xcex1 and levovirin, and a combination of peginterferon-xcex1 and levovirin. Interferon-xcex1 includes, but is not limited to, recombinant interferon-xcex12a (such as Roferon interferon available from Hoffmann-LaRoche, Nutley, N.J.), pegylated interferon-xcex12a (Pegasys(trademark)), interferon-xcex12b (such as Intron-A interferon available from Schering Corp., Kenilworth, N.J.), pegylated interferon-xcex12b PegIntron(trademark)), a recombinant consensus interferon (such as interferon alphacon-1), and a purified interferon-xcex1 product. Amgen""s recombinant consensus interferon has the brand name Infergen(copyright). Levovirin is the L-enantiomer of ribavirin which has shown immunomodulatory activity similar to ribavirin. Viramidine is an amidino analog of ribavirin disclosed in WO 01/60379 (assigned to ICN Pharmaceuticals). In accordance with this method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment, and the term xe2x80x9cadministeringxe2x80x9d is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating HCV infection includes in principle any combination with any pharmaceutical composition for treating HCV infection. When a compound of the present invention or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent active against HCV, the dose of each compound may be either the same as or different from the dose when the compound is used alone.
For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with an agent that is an inhibitor of HCV NS3 serine protease, such as LY570310(VX-950). HCV NS3 serine protease is an essential viral enzyme and has been described to be an excellent target for inhibition of HCV replication. Both substrate and non-substrate based inhibitors of HCV NS3 protease inhibitors are disclosed in WO 98/17679, WO 98/22496, WO 98/46630, WO 99/07733, WO 99/07734, WO 99/38888, WO 99/50230, WO 99/64442, WO 00/09543, WO 00/59929, WO 01/74768, WO 01/81325, and GB-2337262. HCV NS3 protease as a target for the development of inhibitors of HCV replication and for the treatment of HCV infection is discussed in B. W. Dymock, xe2x80x9cEmerging therapies for hepatitis C virus infection,xe2x80x9d Emerging Drugs, 6:13-42 (2001).
Ribavirin, levovirin, and viramidine may exert their anti-HCV effects by modulating intracellular pools of guanine nucleotides via inhibition of the intracellular enzyme inosine monophosphate dehydrogenase (IMPDH). IMPDH is the rate-limiting enzyme on the biosynthetic route in de novo guanine nucleotide biosynthesis. Ribavirin is readily phosphorylated intracellularly and the monophosphate derivative is an inhibitor of IMPDH. Thus, inhibition of IMPDH represents another useful target for the discovery of inhibitors of HCV replication. Therefore, the compounds of the present invention may also be administered in combination with an inhibitor of IMPDH, such as VX-497, which is disclosed in WO 97/41211 and WO 01/00622, (assigned to Vertex); another IMPDH inhibitor, such as that disclosed in WO 00/25780 (assigned to Bristol-Myers Squibb); or mycophenolate mofetil [see A. C. Allison and E. M. Eugui, Agents Action, 44 (Suppl.):165 (1993)].
For the treatment of HCV infection, the compounds of the present invention may also be administered in combination with the antiviral agent amantadine (1-aminoadamantane) [for a comprehensive description of this agent, see J. Kirschbaum, Anal. Profiles Drug Subs. 12:1-36 (1983)].
The compounds of the present invention may also be combined for the treatment of HCV infection with antiviral 2xe2x80x2-C-branched ribonucleosides disclosed in R. E. Harry-O""kuru, et al., J. Org. Chem. 62: 1754-1759 (1997); M. S. Wolfe, et al., Tetrahedron Lett., 36: 7611-7614 (1995); and U.S. Pat. No. 3,480,613 (Nov. 25, 1969), the contents of the U.S. patent being incorporated by reference in their entirety. Such 2xe2x80x2-C-branched ribonucleosides include, but are not limited to, 2xe2x80x2-C-methyl-cytidine, 2xe2x80x2-C-methyl-adenosine, 2xe2x80x2-C-methyl-guanosine, and 9-(2-C-methyl-xcex2-D-ribofuranosyl)-2,6-diaminopurine.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d is meant that the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Also included within the present invention are pharmaceutical compositions comprising the novel nucleoside compouinds and derivatives thereof of the present invention in association with a pharmaceutically acceptable carrier. Another example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
Also included within the present invention are pharmaceutical compositions useful for inhibiting RNA-dependent RNA viral polymerase in particular HCV NS5B polymerase comprising an effective amount of a compound of this invention and a pharmaceutically acceptable carrier. Pharmaceutical compositions useful for treating RNA-dependent RNA viral infection in particular HCV infection are also encompassed by the present invention as well as a method of inhibiting RNA-dependent RNA viral polymerase in particular HCV NS5B polymerase and a method of treating RNA-dependent viral replication and in particular HCV replication. Additionally, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of another agent active against RNA-dependent RNA virus and in particular against HCV. Agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha-1, an inhibitor of HCV NS3 serine protease, interferon-xcex1, pegylated interferon-xcex1 (peginterferon-xcex1), a combination of interferon-xcex1 and ribavirin, a combination of peginterferon-xcex1 and ribavirin, a combination of interferon-xcex1 and levovirin, and a combination of peginterferon-xcex1 and levovirin. Interferon-xcex1 includes, but is not limited to, recombinant interferon-xcex12a (such as Roferon interferon available from Hoffmann-LaRoche, Nutley, N.J.), interferon-xcex12b (such as Intron-A interferon available from Schering Corp., Kenilworth, N.J.), a consensus interferon, and a purified interferon-xcex1 product. For a discussion of ribavirin and its activity against HCV, see J. O. Saunders and S. A. Raybuck, xe2x80x9cInosine Monophosphate Dehydrogenase: Consideration of Structure, Kinetics, and Therapeutic Potential,xe2x80x9d Ann. Rep. Med. Chem., 35:201-210 (2000).
Another aspect of the present invention provides for the use of nucleoside compounds and derivatives thereof and their pharmaceutical compositions for the manufacture of a medicament for the inhibition of RNA-dependent RNA viral replication, in particular HCV replication, and/or the treatment of RNA-dependent RNA viral infection, in particular HCV infection. Yet a further aspect of the present invention provides for nucleoside compounds and derivatives thereof and their pharmaceutical compositions for use as a medicament for the inhibition of RNA-dependent RNA viral replication, in particular HCV replication, and/or for the treatment of RNA-dependent RNA viral infection, in particular HCV infection.
The pharmaceutical compositions of the present invention comprise a compound of structural formula I, IV, or XII as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
In practical use, the compounds of structural formulae I, IV, and XII can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Compounds of structural formulae I, IV, and XII may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of structural formulae I, IV, and XII are administered orally.
For oral administration to humans, the dosage range is 0.01 to 1000 mg/kg body weight in divided doses. In one embodiment the dosage range is 0.1 to 100 mg/kg body weight in divided doses. In another embodiment the dosage range is 0.5 to 20 mg/kg body weight in divided doses. For oral administration, the compositions are preferably provided in the form of tablets or capsules containing 1.0 to 1000 milligrams of the active ingredient, particularly, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art. This dosage regimen may be adjusted to provide the optimal therapeutic response.
The compounds of the present invention contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend nucleoside derivatives having the (xcex2-D stereochemical configuration for the five-membered furanose ring as depicted in the structural formula below, that is, nucleoside compounds in which the substituents at C-1 and C-4 of the five-membered furanose ring have the xcex2-stereochemical configuration (xe2x80x9cupxe2x80x9d orientation as denoted by a bold line). 
The stereochemistry of the substituents at the C-2 and C-3 positions of the furanose ring of the compounds of the present invention is denoted either by a dashed line which signifies that the substituent, for example R2 in structural formula VI, has the xcex1 (substituent xe2x80x9cdownxe2x80x9d) configuration or a squiggly line which signifies that the substituent, for example R3 in structural formula VI, can have either the xcex1 (substituent xe2x80x9cdownxe2x80x9d) or xcex2 (substituent xe2x80x9cupxe2x80x9d) configuration.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Some of the compounds described herein may exist as tautomers such as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of structural formulae I, IV, and XII. An example of keto-enol tautomers which are intended to be encompassed within the compounds of the present invention is illustrated below: 
Compounds of structural formulae I, IV, and XII may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase.
Alternatively, any stereoisomer of a compound of the structural formulae I, IV, and XII may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
The stereochemistry of the substituents at the C-2 and C-3 positions of the furanose ring of the novel compounds of the present invention of structural formula XII is denoted by squiggly lines which signifies that substituents Ra, Rb, Rcand Rh can have either the xcex1 (substituent xe2x80x9cdownxe2x80x9d) or xcex2 (substituent xe2x80x9cupxe2x80x9d) configuration independently of one another. 
The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
Also, in the case of a carboxylic acid (xe2x80x94COOH) or alcohol group being present in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols, such as acetate or maleate, can be employed. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.
Preparation of the Nucleoside Compounds and Derivatives of the Invention
The nucleoside compounds and derivatives thereof of the present invention can be prepared following synthetic methodologies well-established in the practice of nucleoside and nucleotide chemistry. Reference is made to the following text for a description of synthetic methods used in the preparation of the compounds of the present invention: xe2x80x9cChemistry of Nucleosides and Nucleotides,xe2x80x9d L. B. Townsend, ed., Vols. 1-3, Plenum Press, 1988, which is incorporated by reference herein in its entirety.
A representative general method for the preparation of compounds of the present invention is outlined in Scheme 1 below. This scheme illustrates the synthesis of compounds of the present invention of structural formula 1-7 wherein the furanose ring has the xcex2-D-ribo configuration. The starting material is a 3,5-bis-O-protected alkyl furanoside, such as methyl furanoside, of structural formula 1-1. The C-2 hydroxyl group is then oxidized with a suitable oxidizing agent, such as a chromium trioxide or chromate reagent or Dess-Martin periodinane, or by Swern oxidation, to afford a C-2 ketone of structural formula 1-2. Addition of a Grignard reagent, such as an alkyl, alkenyl, or alkynyl magnesium halide (for example, MeMgBr, EtMgBr, vinylMgBr, allylMgBr, and ethynylMgBr) or an alkyl, alkenyl, or alkynyl lithium, such as MeLi, across the carbonyl double bond of 1-2 in a suitable organic solvent, such as tetrahydrofuran, diethyl ether, and the like, affords the C-2 tertiary alcohol of structural formula 1-3. A good leaving group (such as C1, Br, and I) is next introduced at the C-1 (anomeric) position of the furanose sugar derivative by treatment of the furanoside of formula 1-3 with a hydrogen halide in a suitable organic solvent, such as hydrogen bromide in acetic acid, to afford the intermediate furanosyl halide 1-4. A C-1 sulfonate, such methanesulfonate (MeSO2Oxe2x80x94), trifluoromethanesulfonate (CF3SO2Oxe2x80x94), or p-toluenesulfonate (xe2x80x94OTs), may also serve as a useful leaving group in the subsequent reaction to generate the glycosidic (nucleosidic) linkage. The nucleosidic linkage is constructed by treatment of the intermediate of structural formula 1-4 with the metal salt (such as lithium, sodium, or potassium) of an appropriately substituted 1H-pyrrolo[2,3-d]pyrimidine 1-5, such as an appropriately substituted 4-halo-1H-pyrrolo[2,3-d]pyrimidine, which can be generated in situ by treatment with an alkali hydride (such as sodium hydride), an alkali hydroxide (such as potassium hydroxide), an alkali carbonate (such as potassium carbonate), or an alkali hexamethyldisilazide (such as NaHMDS) in a suitable anhydrous organic solvent, such as acetonitrile, tetrahydrofuran, 1-methyl-2-pyrrolidinone, or N,N-dimethylformamide (DMF). The displacement reaction can be catalyzed by using a phase-transfer catalyst, such as TDA-1 or triethylbenzylammonium chloride, in a two-phase system (solid-liquid or liquid-liquid). The optional protecting groups in the protected nucleoside of structural formula 1-6 are then cleaved following established deprotection methodologies, such as those described in T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d 3 ed., John Wiley and Sons, 1999. Optional introduction of an amino group at the 4-position of the pyrrolo[2,3-d]pyrimidine nucleus is effected by treatment of the 4-halo intermediate 1-6 with the appropriate amine, such as alcoholic ammonia or liquid ammonia, to generate a primary amine at the C-4 position (xe2x80x94NH2), an alkylamine to generate a secondary amine (xe2x80x94NHR), or a dialkylamine to generate a tertiary amine (xe2x80x94NRRxe2x80x2). A 7H-pyrrolo[2,3-d]pyrimidin-4(3H)one compound may be derived by hydrolysis of 1-6 with aqueous base, such as aqueous sodium hydroxide. Alcoholysis (such as methanolysis) of 1-6 affords a C-4 alkoxide (xe2x80x94OR), whereas treatment with an alkyl mercaptide affords a C-4 alkylthio (xe2x80x94SR) derivative. Subsequent chemical manipulations well-known to practitioners of ordinary skill in the art of organic/medicinal chemistry may be required to attain the desired compounds of the present invention. 
The examples below provide citations to literature publications, which contain details for the preparation of final compounds or intermediates employed in the preparation of final compounds of the present invention. The nucleoside compounds of the present invention were prepared according to procedures detailed in the following examples. The examples are not intended to be limitations on the scope of the instant invention in any way, and they should not be so construed. Those skilled in the art of nucleoside and nucleotide synthesis will readily appreciate that known variations of the conditions and processes of the following preparative procedures can be used to prepare these and other compounds of the present invention. All temperatures are degrees Celsius unless otherwise noted.